JP2684767B2 - Method for producing aminocyanacetamide - Google Patents

Abstract

A process which can be employed on a large scale for the preparation of aminocyanoacetamide is described. This process starts from a cyanoacetic acid ester, which is nitrosated in a first step to give the corresponding hydroxyiminocyanoacetic acid ester, then hydrogenated and converted to the final product using ammonia in a last step.

Description

The present invention relates to a novel process for producing aminocyanacetamide which can be industrially carried out.

Aminocyanacetamide is a key intermediate for the production of eg imidazole, pyridazine, purine or pteridine.

Many methods are known for the production of aminocyanoacetic acid esters.

West German Patent Publication No. 2700733 discloses a method of hydrogenating ethyl hydroxyiminocyanoacetate with Raney nickel catalyst to give ethyl aminocyanoacetate. The yield obtained by this method is 65%.

The yields of the separated products are low, the quality is poor, and a relatively large amount of catalyst is consumed during the regeneration and recycling of the catalyst. Such consumption is unsuitable for industrial implementation.

Logeman et al, Chem, and Ind.
(1980), 541], ethyl hydroxyiminocyanoacetate can be reacted with sodium dithionite using an ethanol solvent to obtain ethylaminocyanoacetate in a yield of 81% (crude yield).

Disadvantages of this method are the occurrence of sulfate precipitation and the use of flammable ethers. This method is difficult to adopt because of the annoying problem of salt precipitation.

In addition, the method of Taylor et al. [Tayler et al, J. Am. Chem. S.
oc.98,2301 (1976)], hydroxyiminocyanoacetic acid benzyl ester is reacted with methanesulfonic acid in two steps using Al-amalgam and an ether solvent,
Yield methanesulfonate of benzyl aminocyanoacetate
Can be obtained at 53%.

Since this method has a troublesome problem of using a mercury catalyst, it cannot be argued that it cannot be industrially adopted.

Smith et al., J. Am. Chem. Soc. 76,608
0 (1954)] also has similar drawbacks. The method involves hydrogenating hydroxyimino cyanacetamide with Al-amalgam to directly give amino cyanacetamide in a yield of 59%.

The subject of the present invention is not the above-mentioned drawbacks, industrially from the starting origin easily available aminocyanacetamide,
Another object of the present invention is to provide a method that can be manufactured with minimal environmental pollution.

This object can be achieved by the method according to claim 1.

The starting point for the process of the present invention is the use of cyanoacetates, which are easy to handle. The method of the present invention, methyl -, ethyl -, propyl -, butyl - or C ₁ -C ₄ alkyl esters, such as t- butyl ester are preferably used.

The cyanoacetic acid ester can be prepared by a known method in the first step [eg, G. Duguay, J. Heterocycl. Chem. 17 , 767 (1980)].
To give hydroxyiminocyanoacetic acid ester. Usual nitrites of alkali metals, especially sodium nitrite, are used as nitrating agents. The reaction is carried out in an acidic medium.

The resulting hydroxyimino cyanate ester usually migrates to the organic layer. This may be separated if necessary, but it is preferably used directly in the next step.

The next step, the hydrogenation of hydroxyiminocyanoacetic acid ester to aminocyanoacetic acid ester, is carried out using hydrogen in the presence of a platinum catalyst. A preferred platinum catalyst is
1 to 20 platinum on a fine powder carrier such as carbon, aluminum oxide, silicon dioxide, barium sulfate or potassium carbonate
It is one supported by weight% or platinum oxide. Among them, the one in which platinum is supported on carbon in an amount of 3 to 10% by weight is excellent.

The platinum catalyst is used in an amount of 3 to 30% by weight, preferably 10 to 15% by weight, based on the hydroxyiminocyanoacetic acid ester.

The hydrogenation conditions are, according to experience, pressures of 1-100 bar,
Especially preferred is 6-10 bar and temperature 0-40 ° C, especially around room temperature.

It is advantageous to use an organic solvent having a low boiling point for the reaction.
Examples of such a solvent include lower aliphatic alcohols such as ethanol, lower carboxylic acid esters such as ethyl acetate, and lower carboxylic acids such as acetic acid.

The reaction time varies depending on the pressure, the temperature and the amount of catalyst, but is about 0.5 to 10 hours.

The great advantage of the production method of the present invention is that the platinum catalyst can be recovered after the reaction and can be reused for the next hydrogenation.

The obtained aminocyanoacetic acid ester may be separated from the reaction solution, but can be directly reacted with ammonia without separation to give the desired product aminocyanoacetamide.

The conversion to aminocyanacetamide is carried out using ammonia water having a concentration of 10 to 40% by weight at a temperature of -20 to 30 ° C, preferably 0 to 5 ° C.

The molar ratio of ammonia to aminocyanoacetic ester is
You can choose between 30: 1 and 1: 1. The preferred range is 10:
1 to 5: 1.

Although a solvent is used for the reaction in the first step, it is possible to replace it by using only aqueous ammonia without using a solvent.

The produced aminocyanacetamide can be obtained in a yield of 70% or more on the basis of cyanoacetate with a purity of 98% or more at a high temperature by performing usual treatment.

As mentioned above, aminocyanoacetic acid ester is an important intermediate of various synthetic products, but since it has poor storage stability, it is necessary to add an acid to the reaction solution after completion of the hydrogenation reaction to give aminocyanoacetic acid ester. Is preferably in the form of a salt. Such salts include tosyl salts, oxalates or methanesulfonates, and tosyl salts are particularly preferred.

These salts have good storage stability, are easy to handle, and can be produced in high purity.

Example 1 Production of ethyl hydroxyimino cyanate from ethyl cyanoacetate 113.7 g (1.0 mol) of ethyl cyanoacetate and 83.2 g (1.2 mol) of sodium nitrite were dissolved in 900 ml of ice water as a solvent. To this solution, 83.0 g of glacial acetic acid was added dropwise at 10 ° C or lower over 30 minutes. This was stirred at 20 ° C. for 4 hours, 100 ml of concentrated hydrochloric acid was added, and the mixture was extracted 4 times with 150 ml of ethyl acetate each.

The organic layer was washed 4 times with 50 ml of ice water each, dried over sodium sulfate, concentrated to 245 g, and kept at 4 ° C. for 12 hours.

The precipitated hydroxyimino ethyl acetate was filtered off, washed with cold ethyl acetate and dried.

As a result, 130.6 g of product was obtained. Yield 91.9%
(Based on ethyl cyanoacetate), melting point 129.5-131 ° C.

Elemental _{analysis: C 5 H 6 N 2 O} 3 Calculated C41.75%, H4.25%, N19.11% Found C42.26%, H4.26%, N19.71% Example 2 hydroxyimino cyanoacetate Preparation of aminocyanoacetic acid methyl ester-tosyl salt from ester Hydroxyiminocyanoacetic acid methyl ester 18.0 g
Dissolve (0.14 mol) in 200 ml of ethanol and add 2.7
Hydrogenated with g 5% Pt / C catalyst under hydrogen pressure 10 bar at room temperature. The reaction mixture is filtered and the filtrate is toluene.
Toluenesulfonic acid monohydrate 26.9g (0.14
Mol) was added and the mixture was concentrated to 340 g and kept at 4 ° C. for 12 hours.

The precipitated aminocyanoacetic acid methyl ester-tosyl salt was filtered off, washed with toluene and dried.

As a result, 36.9 g of a product was obtained in a yield of 89.7% (based on hydroxyiminocyanoacetic acid methyl ester).
Melting point 162.5-164.5 ° C.

Elemental analysis: C ₁₁ H ₁₄ N ₂ O ₂ S Calculated value C45.80%, H49.2%, N9.65% Measured value C46.18%, H4.93%, N9.79% Example 3 Hydroxyiminocyan Production of aminocyanacetic acid ethyl ester-tosyl salt from acetic acid ethyl ester Hydroxyiminocyanacetic acid ethyl ester 20.0 g
Dissolve (0.14 mol) in 200 ml of ethanol and add 2.6 g of 5
Hydrogenation was carried out at room temperature under a hydrogen pressure of 10 bar using a% Pt / C catalyst.

The reaction mixture was filtered, 1200 ml of toluene and 26.9 g (0.14 mol) of toluenesulfonic acid monohydrate were added to the filtrate, and the mixture was concentrated to 330 g and then kept at 4 ° C. for 12 hours.

The precipitated aminocyanoacetic acid ethyl ester tosyl salt was filtered off, washed with toluene and dried.

As a result, 40.0 g of the product was obtained in a yield of 93.4% (based on hydroxyimino cyanic acid ethyl ester).
Melting point, 128-130 ° C.

The product separated by recrystallization from ethyl acetate has a melting point of 13
It was 0 to 131 ° C.

Elemental analysis: C ₁₂ H ₁₆ N ₂ O ₅ S Calculated value C47.44%, H5.42%, N9.21% Measured value C48.00%, H5.37%, N9.33% Example 4 Hydroxyiminocyan Preparation of aminocyanoacetic acid benzyl ester-tosyl salt from benzyl ester Hydroxyiminocyanoacetic acid benzyl ester 20.4 g
Dissolve (0.1 mol) in 200 ml ethanol and add 3.1 g
Was hydrogenated at room temperature under 10 bar hydrogen pressure using 5% Pt / C catalyst. The reaction mixture was filtered, 19.2 g (0.1 mol) of toluenesulfonic acid monohydrate was added to the filtrate and concentrated to 150 g, and 400 ml of toluene was further added and concentrated to 230 g,
Hold at 4 ° C for 12 hours.

The precipitated aminocyanoacetic acid benzyl ester tosyl salt was filtered off, washed with toluene and dried.

As a result, 31.2 g of the product was obtained in a yield of 86.3% (based on hydroxyiminoacetic acid benzyl ester). Melting point
171-172 ° C.

The melting point of the product separated by recrystallization from isopropanol was 173-174 ° C.

Elemental analysis: C ₁₇ H ₁₈ N ₂ O ₅ S Calculated value C55.6%, H4.95%, N7.82% Measured value C56.38%, H5.01%, N7.73% Example 5 Hydroxyiminocyano Preparation of aminocyanoacetic acid-t-butyl ester-tosyl salt from acetic acid-t-butyl ester Hydroxyiminocyanoacetic acid-t-butyl ester 2
1.3 g (0.1 g mol) was dissolved in 200 ml of ethanol and hydrogenated with 3.2 g of 5% Pt / C catalyst under hydrogen pressure of 10 bar at room temperature. The reaction mixture was filtered, and the filtrate was mixed with toluene (500 ml) and toluenesulfonic acid monohydrate (19.0 g).
(0.1 mol) was added, the mixture was concentrated to 204 g, and then kept at 4 ° C. for 12 hours.

The precipitated aminocyanoacetic acid-t-butyl ester-tosyl salt was filtered off, washed with toluene and dried.

As a result, 16.2 g of a product was obtained in a yield of 51.1% (based on hydroxyimino cyanic acid-t-butyl ester). 124-126 ° C.

The melting point of the product separated by recrystallization from ethyl acetate / ethanol (3: 1) was 128-129.5 ° C.

Elemental analysis: C ₁₄ H ₂₀ N ₂ O ₅ S Calculated value C51.15%, H6.21%, N8.65% Measured value C51.24%, H6.14%, N8.54% Example 6 Ethyl cyanoacetate Preparation of aminocyanoacetic acid ethyl ester-tosyl salt from ester 17.1 g (0.1 mol) of cyanoacetic acid ethyl ester and 12.4 g (0.18 mol) of sodium nitrite were dissolved in 135 ml of ice water, to which 12.5 g (0.21 mol) of glacial acetic acid was added. The solution was added dropwise at 10 ° C over 10 minutes. The solution was stirred at 20 ° C for 1 hour and concentrated hydrochloric acid
15 ml was added and the mixture was extracted 4 times with 50 ml of ethyl acetate each. The organic layer was washed with 15 ml of ice water to neutralize, dried over sodium sulfate, and concentrated to 200 g. 3.2 g of this solution Pt / C
Hydrogenation was carried out at room temperature under a hydrogen pressure of 10 bar using a (5%) catalyst.

The reaction mixture was filtered, and a solution prepared by dissolving 28.8 g (0.15 mol) of toluenesulfonic acid monohydrate in 25 g of methanol was added to the filtrate and concentrated to 120 g.
After concentrating to 55 g, it was kept at 4 ° C. for 12 hours.

The precipitated aminocyanoacetic acid ethyl ester-tosyl salt was filtered off, washed with toluene and then dried.

Recrystallization from ethyl acetate gave 33.7 g of product. Yield 74.9% (based on cyanoacetic acid ethyl ester).

Example 7 Preparation of aminocyanacetamide from hydroxyiminocyanoacetic acid methyl ester 38.6 g of hydroxyiminocyanoacetic acid methyl ester
Dissolve (0.3 mol) in 200 ml of methanol and add 3.1 g
With Pt / C (5%) catalyst under hydrogen pressure of 10 bar,
Hydrogenated at room temperature. The reaction mixture was filtered and the filtrate was cooled with ice water 15
ml was added, and at 0 ° C, 9.0 g of ammonia was added to methanol 25
It was added to the solution dissolved in g. The reaction mixture was stirred at 0 ° C for 3
Stirred for 0 minutes.

The precipitated aminocyanacetamide was filtered off, washed with toluene and then dried.

This gave 18.4 g of product, mp 119.5-120.5 ° C. On the other hand, the filtrate was concentrated to 150 ml, 450 ml of toluene was added, and the mixture was concentrated to 300 ml and kept at 4 ° C. for 12 hours. The precipitated aminocyanacetamide was filtered off, washed with toluene and then dried. This gave 6.0 g of product, mp 112-115 ° C.

Overall yield: 82.0% (hydroxyimino cyan acid methyl ester standards) Elemental analysis: C ₃ H ₅ N ₃ O Calculated C36.2%, H5.1%, N40.5% Found C36.4%, H5 .1%, N42.4% Example 8 Production of aminocyanacetamide from cyanoacetic acid methyl ester (direct synthesis) 40.0 g (0.40 mol) of cyanoacetic acid methyl ester and 33.5 g (0.48 mol) of sodium nitrite were added to 300 ml of water. Dissolve
To this, 31.8 g (0.53 mol) of glacial acetic acid was added dropwise at 10 ° C over 20 minutes. This solution was stirred at 20 ° C for 1 hour and then concentrated hydrochloric acid
50.6 g (0.5 mol) was added and the mixture was extracted 6 times with 50 ml of ethyl acetate each time.

The organic layer was washed twice with 50 ml of water each time to neutral, dried over sodium sulfate and then concentrated to 150 ml and 100 ml of methanol was added. The solution was hydrogenated with 5.1 g of Pt / C (5%) catalyst at room temperature under hydrogen pressure of 6-10 bar.

The reaction mixture was filtered, 15 ml of water was added to the filtrate, and 36.7 g (2.2 mol) of ammonia was added to methanol at 0-5 ° C.
It was added to a solution dissolved in 0 ml. After 1 hour, the precipitated product was filtered off, washed with methanol and dried.

This gave 20.4 g of aminocyanacetamide with a melting point of 121-122 ° C. On the other hand, when the filtrate was concentrated to 50 g, cooled, and filtered again, the product having a melting point of 120 to 121 ° C.
8.7 g was obtained.

Overall yield: 73.2% (based on cyanoacetic acid methyl ester)

Claims (6)

(57) [Claims] 1. A cyanoacetic acid (C ₁ -C ₄ ) alkyl ester or a cyanoacetic acid arylalkyl ester is nitrated in the presence of an alkali metal nitrite to give a corresponding hydroxyiminocyanoacetic acid ester, which is, if necessary, Separated or directly without separation, hydrogen reduction in the presence of a platinum catalyst to give an aminocyanoacetic acid ester, which may be separated as necessary or, without separation, reacted with aqueous ammonia to give the desired product. And a method for producing aminocyanacetamide. 2. The method according to claim 1, wherein the platinum catalyst is platinum oxide, or a carrier composed of aluminum oxide, silicon dioxide, barium sulfate, calcium carbonate, or carbon with 1 to 20% by weight of platinum supported thereon. . 3. Hydrogenation at a pressure of 1-100 bar and a temperature of 0.
The method according to claim 1 or 2, which is carried out under the condition of -40 ° C. 4. The process according to claim 1, wherein a lower aliphatic alcohol, a lower aliphatic carboxylic acid ester or a lower aliphatic carboxylic acid is used as a solvent when hydrogenating. 5. The method according to claim 1, wherein the reaction with aqueous ammonia is carried out at a temperature of −20 to 30 ° C. 6. The method according to claim 1, wherein 1 to 30 molar equivalents of ammonia are used per 1 molar equivalent of aminocyanoacetic acid ester in the reaction with aqueous ammonia.